Sunitinib is a potent multi-targeted kinase inhibitor that is efficacious in the treatment of cancers, most notably renal cell carcinoma and GI stroma tumor as approved by FDA. It is also undergoing clinical trials in a number of other cancers. Its structure is an indolinone derivative characterized by a basic diethylaminoethyl side chain. Although Sunitinib is very efficacious, its application is hampered by the side effects. The most common and severe toxicity in clinic is neutropenia and fatigue.

This invention describes a novel class of Sunitinib derivatives with a cyclic side chain replacing the diethylaminiethyl side chain of Sunitinib. They are designed to overcome the fatigue problem of Sunitinib by improving its selectivity. Recently, a proteomic study of a Sunitinib analog, SU6668 found that SU6668 inhibits, among other proteins, AMPK (Godl et al, Cancer Res 2005, 65, 6919). Since AMPK is a key sensor of fuel and energy status in skeletal muscle (see review by Hardie and Sakamoto, Physiology 2006, 21, 48-60), it is hypothesized that inhibition of AMPK might be the cause of the clinically observed fatigue toxicity of Sunitinib. Thus, the cyclic derivatives of Sunitinib are designed to reduce the inhibitory activity of AMPK, thereby alleviating the fatigue problem of Sunitinib